ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.115A>G (p.Thr39Ala) (rs779297339)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164338 SCV000214970 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416278 SCV000493644 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Color RCV000164338 SCV000292177 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000231502 SCV000799077 uncertain significance Ataxia-telangiectasia syndrome 2018-04-03 criteria provided, single submitter clinical testing
GeneDx RCV000416278 SCV000564602 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.115A>G at the cDNA level, p.Thr39Ala (T39A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr39Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr39Ala occurs at a position that is conserved through mammals and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Thr39Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000231502 SCV000282865 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 39 of the ATM protein (p.Thr39Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs779297339, ExAC 0.004%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 184988). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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